tbuckley/cabot-search huggingface dataset:
Uncoupling CD4+ TIL-Mediated Tumor Killing from JAK-Signaling in Melanoma
Authors: Arianna Draghi, Mario Presti, Agnete W.P. Jensen, Christopher A. Chamberlain, Benedetta Albieri, Anne-Christine K. Rasmussen, Mads H. Andersen, Michael D. Crowther, Inge Marie Svane, Marco Donia
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Impaired MHCI-presentation and insensitivity to immune effector molecules are common features of immune checkpoint blockade (ICB)-resistant tumors and can be, respectively, associated with loss of β2 microglobulin (B2M) or impaired IFNγ signaling. Patients with ICB-resistant tumors can respond to alternative immunotherapies, such as infusion of autologous tumor-infiltrating lymphocytes (TIL). CD4+ T cells can exert cytotoxic functions against tumor cells; however, it is unclear whether CD4+ T-cell responses can be exploited to improve the clinical outcomes of patients affected by ICB-resistant tumors. Experimental Design: Here, we exploited CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 gene editing to reproduce immune-resistant tumor phenotypes via gene knockout (KO). To determine the role of cytotoxic CD4+ TILs in ICB-resistant tumors, we investigated CD4+ TIL-mediated cytotoxicity in matched pairs of TILs and autologous melanoma cell lines, used as a model of patient-specific immune-tumor interaction. Around 40% of melanomas constitutively express MHC Class II molecules; hence, melanomas with or without natural constitutive MHC Class II expression (MHCIIconst+ or MHCIIconst−) were used. Results: CD4+ TIL-mediated cytotoxicity was not affected by B2M loss but was dependent on the expression of CIITA. MHCIIconst+ melanomas were killed by tumor-specific CD4+ TILs even in the absence of IFNγ-mediated MHCII upregulation, whereas IFNγ was necessary for CD4+ TIL-mediated cytotoxicity against MHCIIconst- melanomas. Notably, although tumor-specific CD4+ TILs did not kill JAK1KO MHCIIconst- melanomas even after IFNγ stimulation, sensitivity to CD4+ TIL-mediated cytotoxicity was maintained by JAK1KO MHCIIconst+ melanomas. Conclusions: In conclusion, our data indicate that exploiting tumor-specific cytotoxic CD4+ TILs could help overcome resistance to ICB mediated by IFNγ-signaling loss in MHCIIconst+ melanomas. See related commentary by Betof Warner and Luke, p. 3829
Maveropepimut-S, a DPX-Based Immune-Educating Therapy, Shows Promising and Durable Clinical Benefit in Patients with Recurrent Ovarian Cancer, a Phase II Trial
Authors: Oliver Dorigo, Amit M. Oza, Tanja Pejovic, Prafull Ghatage, Sharad Ghamande, Diane Provencher, Lisa D. MacDonald, Heather Torrey, Valarmathy Kaliaperumal, Walead Ebrahimizadeh, Heather A. Hirsch, Yogesh Bramhecha, Jeannine Villella, Stephan Fiset
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Patients with platinum-resistant ovarian cancer respond poorly to existing therapies. Hence there is a need for more effective treatments. Patients and Methods: The DeCidE1 trial is a multicenter, randomized, open-label, single-arm phase II study to evaluate the safety and effectiveness of maveropepimut-S with cyclophosphamide in patients with recurrent ovarian cancer. Median follow-up for evaluable subjects was 4.4 months. Data were collected from March 2019 to June 2021. Subjects received two injections of 0.25 mL maveropepimut-S 3 weeks apart, followed by one 0.1-mL doses, every 8 weeks up to progression. Oral cyclophosphamide, 50 mg twice daily, was administered in repeating weekly on and off cycles. Results: Twenty-two patients were enrolled. Median age was 58 years (38–78 years). Among the evaluable population, the objective response rate (ORR) was 21% [90% confidence interval (CI), 7.5%–41.9%], with a disease control rate (DCR) of 63% (90% CI, 41.8%–81.3%), including 4 (21%) patients with partial responses, 8 (42%) stable disease, and 7 (37%) progressive disease. The ORRs were consistent across subgroups based on platinum sensitivity, and DCR was higher in the platinum-resistant subpopulation. Four SD patients maintained clinical benefit up to 25 months. Most treatment-related adverse events (TRAE) were grade 1 and 2 (87% of unique events). Most common AEs were injection site reactions. Eight subjects reported grade 3 and no grade 4 AEs. Survivin-specific T-cell responses were observed in treated patients with clinical benefit. Conclusions: Maveropepimut-S with intermittent low-dose cyclophosphamide is well-tolerated, with clinical benefit for patients with recurrent ovarian cancer. Observed responses are irrespective of the platinum status.
Orally Bioavailable Macrocyclic Peptide That Inhibits Binding of PCSK9 to the Low Density Lipoprotein Receptor
Authors: Douglas G. Johns, Louis-Charles Campeau, Puja Banka, An Bautmans, Tjerk Bueters, Elisabetta Bianchi, Danila Branca, Paul G. Bulger, Inne Crevecoeur, Fa-Xiang Ding, Robert M. Garbaccio, Erik D. Guetschow, Yan Guo, Sookhee N. Ha, Jennifer M. Johnston, Hubert Josien, Eunkyung A. Kauh, Kenneth A. Koeplinger, Jeffrey T. Kuethe, Eseng Lai, Christine L. Lanning, Anita Y.H. Lee, Li Li, Anilkumar G. Nair, Edward A. O’Neill, S. Aubrey Stoch, David A. Thaisrivongs, Thomas J. Tucker, Petr Vachal, Kristien van Dyck, Frederic P. Vanhoutte, Bram Volckaert, Dennis G. Wolford, Andy Xu, Tian Zhao, Dan Zhou, Susan Zhou, Xiaohong Zhu, Hratch J. Zokian, Abbas M. Walji, Harold B. Wood
Journal: Circulation (2023)

Background: Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9)-low density lipoprotein receptor interaction with injectable monoclonal antibodies or small interfering RNA lowers plasma low density lipoprotein-cholesterol, but despite nearly 2 decades of effort, an oral inhibitor of PCSK9 is not available. Macrocyclic peptides represent a novel approach to target proteins traditionally considered intractable to small-molecule drug design. Methods: Novel mRNA display screening technology was used to identify lead chemical matter, which was then optimized by applying structure-based drug design enabled by novel synthetic chemistry to identify macrocyclic peptide (MK-0616) with exquisite potency and selectivity for PCSK9. Following completion of nonclinical safety studies, MK-0616 was administered to healthy adult participants in a single rising-dose Phase 1 clinical trial designed to evaluate its safety, pharmacokinetics, and pharmacodynamics. In a multiple-dose trial in participants taking statins, MK-0616 was administered once daily for 14 days to characterize the safety, pharmacokinetics, and pharmacodynamics (change in low density lipoprotein cholesterol). Results: MK-0616 displayed high affinity ( K i = 5pM) for PCSK9 in vitro and sufficient safety and oral bioavailability preclinically to enable advancement into the clinic. In Phase 1 clinical studies in healthy adults, single oral doses of MK-0616 were associated with &gt;93% geometric mean reduction (95% CI, 84–103) of free, unbound plasma PCSK9; in participants on statin therapy, multiple–oral-dose regimens provided a maximum 61% geometric mean reduction (95% CI, 43–85) in low density lipoprotein cholesterol from baseline after 14 days of once-daily dosing of 20 mg MK-0616. Conclusions: This work validates the use of mRNA display technology for identification of novel oral therapeutic agents, exemplified by the identification of an oral PCSK9 inhibitor, which has the potential to be a highly effective cholesterol lowering therapy for patients in need.
A bionic “Trojan horse”-like gene delivery system hybridized with tumor and macrophage cell membrane for cancer therapy
Authors: Tianli Shen, Shuanying Yang, Xiaoyan Qu, Zilu Chen, Lizhong Zeng, Xuejun Sun, Yuyao Lin, Meng Luo, Bo Lei, Chenyang Yue, Chunhong Ma, Nan Hu, Wei Wang, Long Zhang
Journal: Journal of Controlled Release (2023)
Abstract A12: Androgen receptor inhibition is involved in Finasteride-reduced AML cell proliferation
Authors: Pang-Ting Cheng, Chieh-Lin Jerry Teng, Yu-Chiao Cheng, Mei-Chih Chen, Ho Lin
Journal: Blood Cancer Discovery (2023)

Abstract Acute myeloid leukemia (AML) is a top priority type of hematological malignancies to be studied and treated. Androgen receptor (AR) plays important roles in various cancers, such as types of the prostate, breast, liver, and lung. However, the role of AR in leukemia is so far uncertain. Finasteride is a 5 alpha-reductase inhibitor for reduction of cellular 5 alpha-dihydrotestosterone production and commonly used to treat benign prostatic hyperplasia for decades. Here, the data showed that Finasteride treatment significantly decreased the proliferation of AML cell lines, including KG-1 and HL-60. More specific to its impact on androgen’s actions, the authors found that Finasteride inhibited the phosphorylation and activation of AR, while the cell cycle-related proteins such as CDK1, Cyclin A, and p21 were unaffected. Interestingly, the increase of AKT phosphorylation was observed after Finasteride treatment, which is correspondent to the previous findings of mutual correlations between AR inhibition and AKT activation in prostate cancer cells. It implies that AR might play a physiological role in AML cells for proliferation, in which AR closely collaborates with AKT for a balance of regulation. In summary, these results suggest that Finasteride might reduce the proliferation of AML cell lines through AR inhibition. These findings could be helpful to uncover novel AML treatments in the future. Citation Format: Pang-Ting Cheng, Chieh-Lin Jerry Teng, Yu-Chiao Cheng, Mei-Chih Chen, Ho Lin. Androgen receptor inhibition is involved in Finasteride-reduced AML cell proliferation [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A12.
Abstract A15: Computational modeling of methylation impact of AML driver events
Authors: Burcu Gurun, Jeffrey W. Tyner, Emek Demir, Brian J. Druker, Paul T. Spellman
Journal: Blood Cancer Discovery (2023)

Abstract Decades before its clinical onset, epigenetic changes start to accumulate in the progenitor cells of Acute Myelogenous Leukemia– caused by tumor intrinsic driver mutations and tumor extrinsic environmental factors. There are millions of cancer-associated epigenetic changes that are persistent and stable throughout the leukemogenesis and at relapse. By grouping correlated loci into “epigenetic signatures”, we can gain insights on the AML etiology, dynamics as well as mechanisms around the methylation pathways of driver events. We approached this problem in two parts: First, we computationally constructed and analyzed methylation signatures that are associated with DNMT3A and TET2 mutations. Both of them are frequently mutated in AML and they are major causes of changes in the methylation landscape of healthy individuals, conferring a broad risk of transformation to a myeloid malignancy with the serial acquisition of an additional cooperating mutation. We built highly accurate ridge regression models that can differentiate the wild type vs mutant genotypes for DNMT3A and TET2 based on their downstream epigenetic impacts (AUROC 0.9 and 0.8, respectively). It suggests that despite the complicated genetic and epigenetic make-up of post-diagnosis samples, epigenetic regulator mutations’ signatures are distinguishable, and these distinctive marks remain stable over time. We further evaluated methylation loci selected by the models and showed that known downstream targets of DNMT3A such as EVI1/MECOM and AEBP2 (polycomb repressive complex member) were frequently selected by the models. We also identified multiple novel recurrent sites that were previously unassociated with DNMT3A and TET2. Second, we modeled different sources of variations in epigenetic patterns with Topic Modeling. Topic Modeling maps the sparse and high dimensional space of methylation profiles to a small and non-sparse latent space of small number of factors (topics). Each sample is represented as a combination of few topics in that latent space. We annotated these topics with biological and clinical features such as mutation status, prior malignancy, age and gender to shed light on the prevalence and combination of the mutations and other extrinsic factors present at the time of diagnosis. In the future, we aim to identify the etiologies of new signatures to inform detection, monitoring, risk stratifying and drug response studies for AML patients and track these changes throughout leukemogenesis in early detection cohorts. Citation Format: Burcu Gurun, Jeffrey W. Tyner, Emek Demir, Brian J. Druker, Paul T. Spellman. Computational modeling of methylation impact of AML driver events [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A15.
Abstract A42: SLC25A51 impacts drug sensitivity in AML cells by sustaining mitochondrial oxidative flux
Authors: Mu-Jie Lu, Jonathan Busquets, Valeria Impedovo, Yu-Tai Chang, William Matsui, Stefano Tiziani, Xiaolu Cambronne
Journal: Blood Cancer Discovery (2023)

Abstract SLC25A51 imports oxidized NAD+ into the mitochondrial matrix and is required for sustaining oxidative metabolism in human mitochondria. We observed that higher expression of SLC25A51 correlated with poorer survival in Acute Myeloid Leukemia (AML) patient data. Given AML’s dependency on oxidative cell metabolism, we sought to determine the role SLC25A51 may serve in this disease. We found that depleting SLC25A51 in AML cells led to increased apoptosis, as well as prolonged survival in a xenograft model. Metabolic flux analyses indicated that depletion of SLC25A51 shunted flux away from oxidative pathways and promoted glutamine utilization for reductive carboxylation to support aspartate production. Consequently, SLC25A51 loss sensitized AML cells to glutamine deprivation and glutaminase inhibitor CB-839. Together, the work highlights connections between SLC25A51 and oxidative mitochondrial flux in AML. We identified a rationale for targeting SLC25A51 in myeloid cancers with potential for a therapeutic window, especially when coupled with glutaminase inhibition. Citation Format: Mu-Jie Lu, Jonathan Busquets, Valeria Impedovo, Yu-Tai Chang, William Matsui, Stefano Tiziani, Xiaolu Cambronne. SLC25A51 impacts drug sensitivity in AML cells by sustaining mitochondrial oxidative flux [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A42.
Abstract IA22: Myeloproliferative neoplasms: Inflammation and treatment
Authors: Ruben Mesa
Journal: Blood Cancer Discovery (2023)

Abstract Myeloproliferative neoplasms have a prevalence of around 350,000 in the USA and include the diagnoses of essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). These clonal neoplasms share core set of acquired driver mutations in JAK2, calreticulin (CALR), and MPL which all lead to constitutive activation of the JAK-STAT pathway. Additionally, a range of somatic mutations may occur which impact disease phenotype as risk of progression (such as ASXL1, IDH 1 &amp; 2, EZH2 2 etc). The burden of these illnesses include a predisposition to thrombosis or bleeding, a range of challenging symptoms (from spleen pain, to hypermetabolic symptoms, pruritus, fatigue, bone pain), splenomegaly, cytopenias, and potential progression to acute myeloid leukemia. Although the origin of these diseases are anchored in a clonal neoplastic process, inflammation potentially plays a role in the risk of thrombosis, the origin of many of the difficult symptoms, potential contribution to cytopenias, and the potential risk of progression from ET/PV to MF, or from MF to AML. A spectrum of cytokines have been found to be elevated in MPNs (especially in MF), with elevation of certain ones negatively impacting prognosis including IL-8, IL-2R, IL-12, IL-15. Therapy of MPNs now includes non-specific cytoreduction (i.e. hydroxyurea for ET-PV), long acting interferons (i.e. ropegylated interferon a2b for polycythemia vera), and JAK inhibition with ruxolitinib (inhibits JAK1 and JAK2), fedratinib (JAK2 and FLT3), pacritinib (inhibits JAK2, FLT3, IRAK1, and ACVR1), and momelotinib (inhibits JAK1, JAK2, ACVR1). The JAK inhibitors have made a significant impact on decreasing the burden MPN patients face by decreasing splenomegaly (and its associated symptom burden), by decreasing MPN associated symptoms, and by improving survival. The mechanism of improved survival is not fully understood but may include a decrease in marrow inflammation and perhaps decreasing the mutagenic pressure that leads to additional somatic mutations such as ASXL1 that leads to AML. Hepcidin associated with inflammation is dually being investigated as means to decrease erythrocytosis in PV with hepcidin mimetics (i.e. rusferatide), and to improve MF associated anemia by inhibiting hepcidin (momelotinib or pacritinib by ACVR1 inhibition). Inflammation as both a driver of disease burden and progression, as well as a viable therapeutic target remains an important focus of investigation and interventional trials. Citation Format: Ruben Mesa. Myeloproliferative neoplasms: Inflammation and treatment [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr IA22.
Abstract A20: Inflammation remodels the immune microenvironment in acute myeloid leukemia
Authors: Audrey Lasry, Bettina Nadorp, Maarten Fornerod, Deedra Nicolet, Huiyun Wu, Christopher J Walker, Zhengxi Sun, Matthew T Witkowski, Anastasia N Tikhonova, Maria Guillamot, Geraldine Cayanan, Anna Yeaton, Tanja A Gruber, Ann-Kathrin Eisfeld, Iannis Aifantis
Journal: Blood Cancer Discovery (2023)

Abstract Acute myeloid leukemia (AML) is a hematopoietic malignancy with poor prognosis and limited treatment options. Here we provide a comprehensive single cell RNA-Sequencing census of the bone marrow immune microenvironment in adult and pediatric AML patients. We characterize unique inflammation signatures in a subset of AML patients, associated with inferior outcomes. We identify atypical B cells, a dysfunctional B cell subtype enriched in high-inflammation AML patients, as well as an increase in CD8+ GZMK+ and regulatory T cells, accompanied by a reduction in T cell clonal expansion. We derive an inflammation-associated gene score (iScore) that associates with poor survival outcomes in AML patients. Addition of the iScore refines current risk stratifications for AML patients and may enable identification of patients in need of more aggressive treatment. This work provides a first framework for classifying AML patients based on their immune microenvironment and a rationale for consideration of the inflammatory state in clinical settings. Citation Format: Audrey Lasry, Bettina Nadorp, Maarten Fornerod, Deedra Nicolet, Huiyun Wu, Christopher J Walker, Zhengxi Sun, Matthew T Witkowski, Anastasia N Tikhonova, Maria Guillamot, Geraldine Cayanan, Anna Yeaton, Tanja A Gruber, Ann-Kathrin Eisfeld, Iannis Aifantis. Inflammation remodels the immune microenvironment in acute myeloid leukemia [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A20.
Abstract A04: Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia
Authors: Eric Wang, Omar Abdel-Wahab, Robert K Bradley, Jose Mario Bello, Won Jun Kim, Carine Bossard
Journal: Blood Cancer Discovery (2023)

Abstract Therapy resistance is a major challenge in the treatment of cancer. Here, we performed CRISPR/Cas9 screens across a broad range of therapies used in acute myeloid leukemia to identify genomic determinants of drug response. Our screens uncovered a selective dependency on RNA splicing factors whose loss preferentially enhanced response to the BCL2 inhibitor venetoclax. Loss of the splicing factor RBM10 augmented response to venetoclax in leukemia yet was completely dispensable for normal hematopoiesis. Combined RBM10 and BCL2 inhibition led to mis-splicing and inactivation of the inhibitor of apoptosis XIAP and downregulation of BCL2A1, an anti-apoptotic protein implicated in venetoclax resistance. A novel inhibitor of splicing kinase families CLKs and DYRKs led to aberrant splicing of key splicing and apoptotic factors that synergized with venetoclax and overcame resistance to BCL2 inhibition. Our findings underscore the importance of splicing in modulating response to therapies and provide a strategy to improve venetoclax-based treatments. Citation Format: Eric Wang, Omar Abdel-Wahab, Robert K Bradley, Jose Mario Bello, Won Jun Kim, Carine Bossard. Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A04.
Abstract A16: Multi-omic analyses in genetically engineered mice reveal distinct and opposite effects of leukemogenic Idh and Tet2 mutations in hematopoietic stem and progenitor cells
Authors: Jerome Fortin, Ming-Feng Chiang, Cem Meydan, Jonathan Foox, Parameswaran Ramachandran, Julie Leca, Francois Lemonnier, Wanda Y. Li, Miki S. Gams, Takashi Sakamoto, Mandy Chu, Chantal Tobin, Eric Laugesen, Troy M. Robinson, Annick You-Ten, Daniel J. Butler, Thorsten Berger, Mark D. Minden, Ross L. Levine, Cynthia J. Guidos, Ari M. Melnick, Christopher E. Mason, Tak W. Mak
Journal: Blood Cancer Discovery (2023)

Abstract Mutations in IDH1, IDH2, and TET2 are recurrently observed in myeloid neoplasms. IDH1 and IDH2 encode isocitrate dehydrogenase isoforms, which normally catalyze the conversion of isocitrate to α-ketoglutarate (α-KG). Oncogenic IDH1/2 mutations confer neomorphic activity, leading to the production of D-2-hydroxyglutarate (D-2-HG), a potent inhibitor of α-KG-dependent enzymes which include the TET methylcytosine dioxygenases. Given their mutual exclusivity in myeloid neoplasms, IDH1, IDH2, and TET2 mutations may converge on a common oncogenic mechanism. Contrary to this expectation, we observed that they have distinct, and even opposite, effects on hematopoietic stem and progenitor cells in genetically engineered mice. Endogenous Idh2R172K caused much higher D-2-HG production compared to Idh1R132H and Idh2R140Q. This led to profound alterations in hematopoietic progenitor differentiation and to the development of myelodysplastic syndrome-like disease, with shorter survival compared to Tet2−/- mice. Epigenetic and single-cell transcriptomic analyses revealed that Idh2R172K and Tet2 loss-of-function have divergent and opposite effects on the expression and activity of key hematopoietic and leukemogenic regulators. Notably, chromatin accessibility and transcriptional deregulation in Idh2R172K cells were partially disconnected from DNA methylation alterations. These results highlight unanticipated divergent effects of IDH1/2 and TET2 mutations, which may inform the development of genotype-specific therapies. Citation Format: Jerome Fortin, Ming-Feng Chiang, Cem Meydan, Jonathan Foox, Parameswaran Ramachandran, Julie Leca, Francois Lemonnier, Wanda Y. Li, Miki S. Gams, Takashi Sakamoto, Mandy Chu, Chantal Tobin, Eric Laugesen, Troy M. Robinson, Annick You-Ten, Daniel J. Butler, Thorsten Berger, Mark D. Minden, Ross L. Levine, Cynthia J. Guidos, Ari M. Melnick, Christopher E. Mason, Tak W. Mak. Multi-omic analyses in genetically engineered mice reveal distinct and opposite effects of leukemogenic Idh and Tet2 mutations in hematopoietic stem and progenitor cells [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A16.